Micronized tanaproget, compositions, and methods of preparing the same

ABSTRACT

The present invention provides compositions, desirably pharmaceutical compositions, containing micronized tanaproget. The compositions can also contain microcrystalline cellulose, croscarmellose sodium, anhydrous lactose, magnesium stearate, micronized edetate calcium disodium hydrous, and micronized sodium thiosulfate pentahydrate. The compositions are useful in contraception and hormone replacement therapy and in the treatment and/or prevention of uterine myometrial fibroids, benign prostatic hypertrophy, benign and malignant neoplastic disease, dysfunctional bleeding, uterine leiomyomata, endometriosis, polycystic ovary syndrome, and carcinomas and adenocarcinomas of the pituitary, endometrium, kidney, ovary, breast, colon, and prostate and other hormone-dependent tumors, and in the preparation of medicaments useful therefor. Additional uses include stimulation of food intake.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/411,523, filed Apr. 26, 2006, which claims the benefit of thepriority of U.S. Provisional Patent Application No. 60/675,550, filedApr. 28, 2005, now expired. These priority applications are herebyincorporated by reference

BACKGROUND OF THE INVENTION

Intracellular receptors (IR) form a class of structurally related generegulators known as “ligand dependent transcription factors”. Thesteroid receptor family is a subset of the IR family, including theprogesterone receptor (PR), estrogen receptor (ER), androgen receptor(AR), glucocorticoid receptor (GR), and mineralocorticoid receptor (MR).

The natural hormone, or ligand, for the PR is the steroid progesterone,but synthetic compounds, such as medroxyprogesterone acetate orlevonorgestrel, have been made which also serve as ligands. Once aligand is present in the fluid surrounding a cell, it passes through thecell membrane via passive diffusion, and binds to the IR to create areceptor/ligand complex. This complex binds to specific gene promoterspresent in the cell's DNA. Once bound to the DNA, the complex modulatesthe production of mRNA and protein encoded by that gene.

A compound that binds to an IR and mimics the action of the naturalhormone is termed an agonist, whilst a compound which inhibits theeffect of the hormone is an antagonist.

PR agonists (natural and synthetic) are known to play an important rolein the health of women. PR agonists are used in birth controlcompositions, typically in the presence of an ER agonist, alternativelythey may be used in conjunction with a PR antagonist. ER agonists areused to treat the symptoms of menopause, but have been associated with aproliferative effect on the uterus which can lead to an increased riskof uterine cancers. Co-administration of a PR agonist reduces/ablatesthat risk.

Tanaproget,5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1H-pyrrole-2-carbonitrile,is a progesterone receptor modulator and is effective in contraception,hormone replacement therapy, and treating carcinomas andadenocarcinomas, dysfunctional bleeding, uterine leiomyomata,endometriosis, and polycystic ovary syndrome.

What is needed in the art are compositions containing tanaproget foradministration to a mammalian subject.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides compositions containingmicronized tanaproget or a pharmaceutically acceptable salt thereof,microcrystalline cellulose, croscarmellose sodium, anhydrous lactose,magnesium stearate, micronized edetate calcium disodium hydrous, andmicronized sodium thiosulfate pentahydrate.

In still a further aspect, the present invention provides processes forpreparing compositions containing micronized tanaproget.

Other aspects and advantages of the present invention are describedfurther in the following detailed description of the preferredembodiments thereof.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides effective pharmaceutical compositionscontaining micronized tanaproget. The micronized tanaproget can bereadily formulated into an oral dosage unit, and is particularly wellsuited for a directly compressible unit. The inventors have found thattablets or caplets prepared by direct compression of or capsulescontaining the micronized tanaproget compositions of the inventionexhibited rapid and complete drug release, as compared to non-micronizedtanaproget. Thus, the compositions of the invention provide for fastdrug release.

Briefly, tanaproget is micronized under nitrogen and conventionalmicronizing techniques, for example with a Trost or jet mill, applied tonon-micronized tanaproget. One method of preparation of non-micronizedtanaproget is described in U.S. Pat. No. 6,436,929, and generally in USPatent Application Publication No. 2005/0272702, published Dec. 8, 2005.However, the invention is not limited to the method by which thenon-micronized tanaproget is produced.

In another embodiment, non-micronized tanaproget is purified byrecrystallization. In one embodiment, non-micronized tanaproget isrecrystallized from acetone and water. In a further embodiment, thetanaproget is dissolved in acetone, the acetone solution heated, wateradded to the heated acetone solution, and the acetone/water solutioncooled to provide purified tanaproget. This purification specificallyincludes dissolving crude tanaproget in acetone and heating the solutionto about 45 to about 51° C. After circulating the heated solutionthrough a carbon filter for at least about 4 hours, the filteredsolution was concentrated using procedures known to those of skill inthe art. After adding water to the concentrated solution, in oneembodiment at a rate which does not cool the refluxing acetone solution,the acetone/water solution was cooled to about −6 to about 0° C. In oneembodiment, the acetone/water solution was cooled at a rate of less thanabout 0.5° C./minute. After holding the batch at the reduced temperaturefor at least about 3 hours, the precipitated, purified tanaproget iscollected using filtration. The collected solid is washed with awater/acetone mixture, in one embodiment washed twice with a 1:1water/acetone mixture. The washed purified tanaproget is then dried atless than 35° C. for about 4 hours. Further drying at less than about50° C. was performed to remove residual acetone/water as measured byspectroscopic methods.

In one embodiment, micronized tanaproget prepared according to thepresent invention has a particle size of less than about 20 μm, lessthan about 15 μm, or less than about 10 μm. In a further embodiment, 90%of the particles are less than or equal to about 20 μm and 50% are lessthan or equal to about 15 μm as determined by the Malvern method, whichis readily understood by one of skill in the art.

The micronized tanaproget encompasses tautomeric forms of tanaproget andsalts derived from pharmaceutically or physiologically acceptable acids,bases, alkali metals and alkaline earth metals. The present inventionalso includes derivatives of tanaproget, including, but not limited to,esters, carbamates, sulfates, ethers, oximes, carbonates, and the like.

Physiologically acceptable acids include those derived from inorganicand organic acids. A number of inorganic acids are known in the art andinclude hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, andphosphoric acids, among others. Similarly, a variety of organic acidsare known in the art and include, without limitation, lactic, formic,acetic, fumaric, citric, propionic, oxalic, succinic, glycolic,glucuronic, maleic, furoic, glutamic, benzoic, anthranilic, salicylic,tartaric, malonic, mallic, phenylacetic, mandelic, embonic,methanesulfonic, ethanesulfonic, panthenoic, benzenesulfonic,toluenesulfonic, stearic, sulfanilic, alginic, and galacturonic acids,among others.

Physiologically acceptable bases include those derived from inorganicand organic bases. A number of inorganic bases are known in the art andinclude aluminum, calcium, lithium, magnesium, potassium, sodium, andzinc sulfate or phosphate compounds, among others. A number of organicbases are known in the art and include, without limitation,N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, and procaine, among others.

Physiologically acceptable alkali salts and alkaline earth metal saltscan include, without limitation, sodium, potassium, calcium andmagnesium salts in the form of esters, and carbamates.

These salts, as well as the nonmicronized and micronized tanaproget canbe in the form of esters, carbamates and other conventional “pro-drug”forms, which, when administered in such form, convert to the activemoiety in vivo. In one embodiment, the prodrugs are esters. See, e.g.,B. Testa and J. Caldwell, “Prodrugs Revisited: The “Ad Hoc” Approach asa Complement to Ligand Design”, Medicinal Research Reviews,16(3):233-241, ed., John Wiley & Sons (1996).

Micronized tanaproget discussed herein also encompasses “metabolites”which are unique products formed by processing tanaproget by the cell orpatient. In one embodiment, metabolites are formed in vivo.

In one embodiment, the compositions of the invention are prepared by drymixing micronized tanaproget, based upon the total weight of the unitdose, with the other components of the composition. In anotherembodiment, the compositions of the invention are prepared by wet mixingmicronized tanaproget, based upon the total weight of the unit dose,with the other components of the composition.

As referred to herein below, the term “wt/wt” refers to the weight ofone component based on the total weight of the components utilized inthe composition. In one embodiment, wt/wt refers to the weight of onecomponent based on the total weight of the composition. In anotherembodiment, wt/wt refers to the weight of one component based on thetotal weight of the final tablet or caplet. In one embodiment, thisratio does not include the weight of the capsule, the weight of anyfiller utilized in the capsule, and seal coating, if so utilized.

A. The Composition of the Invention

The compositions of the present invention are formulated to providerapid release of tanaproget, while simultaneously being stable underconditions of storage. In one embodiment, the composition containsmicronized tanaproget, or a pharmaceutically acceptable salt thereof,microcrystalline cellulose (MCC), croscarmellose sodium, anhydrouslactose, magnesium stearate, micronized edetate calcium disodium hydrous(EDTA), and micronized sodium thiosulfate pentahydrate. In a furtherembodiment, the tanaproget is intragranular. In still a furtherembodiment, the tanaproget, MCC, anhydrous lactose, EDTA, and sodiumthiosulfate pentahydrate are intragranular.

In one embodiment, micronized tanaproget is present in the compositionof the invention in an amount from 0.15% to about 0.50% wt/wt of thecomposition. This amount may be varied, depending upon the amount ofmicronized tanaproget to be delivered to a patient. The desiredtherapeutic regimen can be taken into consideration when formulating thecomposition of the invention. In another embodiment, an overage oftanaproget is utilized, e.g., a 5% overage. For example, micronizedtanaproget is present in the formulation at about 0.15% wt/wt based uponthe total weight of the unit dose. In another example, micronizedtanaproget is present in the composition at about 0.23% wt/wt based uponthe total weight of the unit dose. In a further example, micronizedtanaproget is present in the composition at about 0.31% wt/wt based uponthe total weight of the unit dose. In yet another example, micronizedtanaproget is present in the composition at about 0.5% wt/wt based uponthe total weight of the unit dose.

The composition also includes microcrystalline cellulose (MCC), in oneembodiment at about 30 to about 50% wt/wt of the composition. In oneexample, MCC is present in the composition at about 30% wt/wt. Inanother example, MCC is present in the composition at about 40% wt/wt.In a further example, MCC is present in the composition at about 50%wt/wt.

The composition also includes croscarmellose sodium, in one embodimentat about 2 to about 6% wt/wt of the composition, in extragranular and/orintragranular forms. In one example, croscarmellose sodium is present atabout 2% wt/wt of the composition. In another example, croscarmellosesodium is present at about 4% wt/wt of the composition. In a furtherexample, croscarmellose sodium is present at about 6% wt/wt of thecomposition.

The composition further includes one or more of an “antioxidant”. By theterm “antioxidant” is meant a compound that is capable or inhibiting orretarding the degradation of the composition of the present invention.In one embodiment, the antioxidant inhibits or retards the degradationof the tanaproget in the composition. Examples of antioxidants that areuseful in the present invention include sodium thiosulfate, sodiummetabisulfite, cysteine, methionine, vitamin E, and edetate calciumdisodium hydrous (EDTA). In a further embodiment, the antioxidant ismicronized prior to use in the present invention.

In one embodiment, the compositions of the invention include EDTA, whichis present at about 0.05 to 0.15% wt/wt of the composition, or about0.05, 0.10, or 0.15% wt/wt of the composition. In one embodiment, theEDTA is micronized and 90% of the particles are less than or equal toabout 35 μm, 50% are less than or equal to about 11 μm, and 10% are lessthan or equal to 3 μm as determined by the Malvern method, which isreadily understood by one of skill in the art.

In one embodiment, sodium thiosulfate pentahydrate is present in thecomposition at about 0.25 to about 0.75% wt/wt, or about 0.25, 0.50 (or0.5), or 0.75% wt/wt. In one embodiment, the sodium thiosulfatepentahydrate is micronized and 90% of the particles are less than orequal to about 31 μm, 50% are less than or equal to about 13 μm, and 10%are less than or equal to 4 μm as determined by the Malvern method,which is readily understood by one of skill in the art.

In one example, the composition includes EDTA at about 0.25% wt/wt andsodium thiosulfate at about 0.25% wt/wt. In another example, thecomposition includes EDTA at about 0.10% wt/wt and sodium thiosulfate atabout 0.50% wt/wt.

In a further example, the composition includes EDTA at about 0.15% wt/wtand sodium thiosulfate at about 0.75% wt/wt.

The composition of the invention also includes anhydrous lactose,typically at about 54 to about 55% wt/wt of the composition. In oneexample, anhydrous lactose is present at about 54% wt/wt of thecomposition. In a further example, anhydrous lactose is present at about55% wt/wt of the composition. In another example, anhydrous lactose ispresent at about 54.8% wt/wt of the composition. In a further example,anhydrous lactose is present at about 54.79% wt/wt of the composition.In still another example, anhydrous lactose is present at about 54.71%wt/wt of the composition. In yet a further example, anhydrous lactose ispresent at about 54.56% wt/wt of the composition.

The composition of the invention further includes magnesium stearate, inone embodiment at about 0.25 to about 0.5% wt/wt. In a furtherembodiment, the composition contains about 0.25% wt/wt of magnesiumstearate. In another embodiment, the composition contains about 0.375%wt/wt of magnesium stearate. In another embodiment, the compositioncontains about 0.5% wt/wt of magnesium stearate. In still anotherembodiment, the composition contains about 0.37% wt/wt of magnesiumstearate. The magnesium stearate can be present in intragranular and/orextragranular forms.

In one embodiment, a composition of the invention includesmicrocrystalline cellulose at about 40% wt/wt of the composition;croscarmellose sodium at about 4% wt/wt of the composition;intragranular magnesium stearate at about 0.37% wt/wt of thecomposition; intragranular anhydrous lactose at about 54 to about 55%wt/wt of the composition; intragranular micronized edetate calciumdisodium hydrous at about 0.10% wt/wt of the composition; andintragranular micronized sodium thiosulfate pentahydrate at about 0.5%wt/wt of the composition.

In another embodiment, the composition can further contain intragranularmicrocrystalline cellulose at about 40% wt/wt of the composition;intragranular croscarmellose sodium at about 2% wt/wt of thecomposition; intragranular magnesium stearate at about 0.19% wt/wt ofthe composition; intragranular anhydrous lactose at about 54 to about55% wt/wt of the composition; intragranular micronized edetate calciumdisodium hydrous at about 0.10% wt/wt of the composition; andintragranular micronized sodium thiosulfate pentahydrate at about 0.5%wt/wt of the composition. The composition can further containextragranular croscarmellose sodium at about 2% wt/wt of the compositionand extragranular magnesium stearate at about 0.19% wt/wt of thecomposition.

In a further embodiment, the composition of the present inventionprovides about 0.15% wt/wt micronized tanaproget, about 40% wt/wtmicrocrystalline cellulose, about 54.87% wt/wt anhydrous lactose, about4% wt/wt croscarmellose sodium, about 0.38% wt/wt magnesium stearate,about 0.1% wt/wt micronized EDTA, and about 0.5% wt/wt micronized sodiumthiosulfate pentahydrate.

In still another embodiment, the composition of the present inventionprovides about 0.23% wt/wt micronized tanaproget, about 40% wt/wtmicrocrystalline cellulose, about 54.79% wt/wt anhydrous lactose, about4% wt/wt croscarmellose sodium, about 0.38% wt/wt magnesium stearate,about 0.1% wt/wt micronized EDTA, and about 0.5% wt/wt micronized sodiumthiosulfate pentahydrate.

In a further embodiment, the composition of the present inventionprovides about 0.31% wt/wt micronized tanaproget, about 40% wt/wtmicrocrystalline cellulose, about 54.71% wt/wt anhydrous lactose, about4% wt/wt croscarmellose sodium, about 0.38% wt/wt magnesium stearate,about 0.1% wt/wt micronized EDTA, and about 0.5% wt/wt micronized sodiumthiosulfate pentahydrate.

In still another embodiment, the composition of the present inventionprovides about 0.46% wt/wt micronized tanaproget, about 40% wt/wtmicrocrystalline cellulose, about 54.56% wt/wt anhydrous lactose, about4% wt/wt croscarmellose sodium, about 0.38% wt/wt magnesium stearate,about 0.1% wt/wt micronized EDTA, and about 0.5% wt/wt of micronizedsodium thiosulfate pentahydrate.

Without limitation as to the method of preparation of a composition ofthe invention, an example of a suitable micronized tanaprogetcomposition is provided in Table 1.

TABLE 1 Component % wt/wt Intragranular micronized tanaproget 0.1546 MCC40.00 anhydrous lactose 54.8706 EDTA 0.10 micronized sodium thiosulfate0.5 pentahydrate micronized croscarmellose sodium 2.00 magnesiumstearate 0.1875 Extragranular croscarmellose sodium 2.00 magnesiumstearate 0.1875

Still a further example of a suitable micronized tanaproget compositionis provided in Table 2.

TABLE 2 Component % wt/wt Intragranular micronized tanaproget 0.2316 MCC40.00 anhydrous lactose 54.7935 EDTA 0.10 micronized sodium 0.5thiosulfate pentahydrate micronized croscarmellose 2.00 sodium magnesiumstearate 0.1875 Extragranular croscarmellose sodium 2.00 magnesiumstearate 0.1875

Another example of a suitable micronized tanaproget composition isprovided in Table 3.

TABLE 3 Component % wt/wt Intragranular micronized tanaproget 0.3088 MCC40.00 anhydrous lactose 54.7163 EDTA 0.10 micronized sodium 0.5thiosulfate pentahydrate micronized croscarmellose 2.00 sodium magnesiumstearate 0.1875 Extragranular croscarmellose sodium 2.00 magnesiumstearate 0.1875

Yet a further example of a suitable micronized tanaproget composition isprovided in Table 4.

TABLE 4 Component % wt/wt Intragranular micronized tanaproget 0.4632 MCC40.00 anhydrous lactose 54.5619 EDTA 0.10 micronized sodium 0.5thiosulfate pentahydrate micronized croscarmellose 2.00 sodium magnesiumstearate 0.1875 Extragranular croscarmellose sodium 2.00 magnesiumstearate 0.1875

The composition of the invention is prepared by mixing micronizedtanaproget, microcrystalline cellulose, croscarmellose sodium,micronized sodium thiosulfate pentahydrate, anhydrous lactose,micronized edetate calcium disodium hydrous, and magnesium stearate. Inone embodiment, the composition is prepared by wet mixing the componentstherein with water. The components of the composition can also be inextragranular or intragranular forms, as determined by one of skill inthe art and the requirements of the process.

A variety of apparatuses can be utilized to perform the process of theinvention and includes bags of small, medium, and large sizes, screensof varying sizes, and blenders, among others.

The process can also include compacting and/or milling the composition,typically using compactors and mills selected by one of skill in theart. The milling step is typically performed on particles of varyingsizes, i.e., large particles, powders, and fine powders to obtain apreferred and more uniform particle size. The milling can includeseveral separating, recycling, and screening steps to obtain the desiredparticle sizes. Drying is generally performed using suitable dryinginstrument selected by one of skill in the art such as a fluid beddryer.

In a further embodiment, the compositions of the present invention canbe prepared by diluting the compositions with excipients. Usefulexcipients for dilution include those set forth below and can includeMCC, croscarmellose sodium, and magnesium stearate.

Compositions containing lesser amounts of tanaproget can preparedaccording to the present invention by diluting compositions containinggreater amounts of tanaproget. In one embodiment, a compositioncontaining 0.01 mg of tanaproget is prepared by diluting a compositioncontaining 0.1, 0.15, 0.2, or 0.3 mg of tanaproget, and desirably bydiluting a composition containing 0.10 mg. In another embodiment, acomposition containing 0.1 mg of tanaproget is prepared by diluting acomposition containing 0.15, 0.2, or 0.3 mg of tanaproget. In yet afurther embodiment, a composition containing 0.15 mg tanaproget isprepared by diluting a composition containing 0.2 or 0.3 mg oftanaproget. In still another embodiment, a composition containing 0.2 mgof tanaproget is prepared by diluting a composition containing 0.3 mg oftanaproget. In another embodiment, the compositions of the inventionprepared by diluting compositions containing higher amounts oftanaproget are diluted with MCC, croscarmellose sodium, magnesiumstearate, and lactose.

In one embodiment, the compositions of the present invention containparticles of an optimal size to permit dissolution of the composition,e.g., the particles are less than or equal to about 100 μm. The sizes ofthe particles of the composition are typically measured by passing thesolid composition through screens of varying sizes. In one embodiment,about 36% of the particles are greater than or equal to about 180 μm. Inanother embodiment, about 46% of the particles are greater than or equalto about 125 μm. In a further embodiment, about 75% of the particles aregreater than or equal to about 45 μm. In still another embodiment, about25% of the particles are less than about 45 μm.

If the particles of the compositions are larger than the optimal sizeand if the same have not yet been encapsulated in a capsule, the samecan be subject to further milling and screening steps, among others, toreduce the particle size.

The process typically includes compressing the composition into a formsuitable for oral administration and is typically a tablet or caplet.When compressed into a tablet or caplet, one of skill in the art wouldreadily be able to select a suitable tablet or caplet press for use inthe present invention. One example of such a press includes the Stokes®B2 Tablet Press, among others.

The tablet prepared according to the present invention can be optionallyencapsulated in a capsule. In one embodiment, the capsule is ahydroxypropyl methylcellulose (hypromellose) capsule. The capsule can beoptionally sealed with the tablet therein or a filler can be added tothe capsule containing tablet. In one embodiment, the filler includesextragranular croscarmellose sodium and magnesium stearate. In a furtherembodiment, the tablet is placed in the capsule prior to adding thefiller.

Optionally, the tablets or caplets are film-coated. Suitablefilm-coatings are known to those of skill in the art. For example, thefilm-coating can be selected from among suitable polymers such ashydroxpropylmethylcellulose, ethyl cellulose, polyvinyl alcohol, andcombinations thereof. Other suitable film-coatings can be readilyselected by one of skill in the art. In one embodiment, the tablet orcaplet is coated with an Opadry™ seal coat. In a further embodiment, thetablet or caplet is coated with an Opadry™ Blue seal coat. Whereapplied, the weight percent of the film coat is generally in the rangeof 2% wt/wt to 6% wt/wt of the tablet or caplet. In one embodiment, theweight percent of the film coat is about 3.5% wt/wt of the tablet orcaplet. Drying of the coating is accomplished by conventional means,e.g., with a fluid bed dryer.

When prepared according to the present invention, the tablets, caplets,capsules, or tablets-in-capsules containing the composition releaseabout 86 to about 99% of tanaproget after about 90 minutes. In a furtherembodiment, 85% of the tanaproget, or about 90%, is released in about 15minutes.

B. Stability of the Compositions of the Invention

The compositions of the present invention are stable over a period ofabout 1 month for samples stored at varying temperatures and humidities.The term stable as used herein refers to the compositions of theinvention which degrade less than about 3%. Typically, it is thetanaproget that degrades in the composition. In one embodiment, thecompositions are stable at about 20° C./50% relative humidity to about45° C./75% relative humidity. In another embodiment, the compositions ofthe invention degrade less than about 3% over a period of greater than 1month at temperatures at or greater than about 25° C. and a relativehumidity at or greater than about 60%.

The compositions of the invention can be stored at reduced temperatures,and in one embodiment, at temperatures of about 5° C. The compositionscan also be stored in the absence of water, air, and moisture. However,storage at room temperature, among other atmospheric conditions, doesnot affect the overall stability of the compositions.

C. Additional Components of the Compositions of the Invention

Other suitable components can be added to the compositions of thepresent invention, provided that the same is not already present, andwill be readily apparent to one of skill in the art. Typically, theadditional components are inert and do not interfere with the functionof the required components of the compositions. The compositions of thepresent invention can thereby further include other adjuvants, syrups,elixirs, diluents, binders, lubricants, surfactants, granulating agents,disintegrating agents, emollients, metal chelators, pH adjustors,surfactants, fillers, disintegrants, and combinations thereof, amongothers.

Adjuvants can include, without limitation, flavoring agents, coloringagents, preservatives, and supplemental antioxidants, which can includeascorbic acid, butylated hydroxytoluene (BHT) and butylatedhydroxyanisole (BHA).

Binders can include, without limitation, cellulose, methylcellulose,hydroxymethylcellulose, carboxymethylcellulose calcium,carboxymethylcellulose sodium, hydroxypropylcellulose,hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,polypropylpyrrolidone, polyvinylpyrrolidone (povidone, PVP), gelatin,gum arabic and acacia, polyethylene glycols, starch, sugars such assucrose, kaolin, dextrose, and lactose, cholesterol, tragacanth, stearicacid, gelatin, casein, lecithin (phosphatides), cetostearyl alcohol,cetyl alcohol, cetyl esters wax, dextrates, dextrin, glycerylmonooleate, glyceryl monostearate, glyceryl palmitostearate,polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives,polyoxyethylene stearates, polyvinyl alcohol, and gelatin, among others.In one embodiment, the binder is povidone.

Lubricants can include light anhydrous silicic acid, talc, stearic acid,sodium lauryl sulfate, magnesium stearate and sodium stearyl furamate,among others. In one embodiment, the lubricant is magnesium stearate.

Granulating agents can include, without limitation, silicon dioxide,starch, calcium carbonate, pectin, crospovidone, and polyplasdone, amongothers.

Disintegrating agents or disintegrants can include starch,carboxymethylcellulose, substituted hydroxypropylcellulose, sodiumbicarbonate, calcium phosphate, calcium citrate, sodium starchglycolate, pregelatinized starch or crospovidone, among others.

Emollients can include, without limitation, stearyl alcohol, mink oil,cetyl alcohol, oleyl alcohol, isopropyl laurate, polyethylene glycol,olive oil, petroleum jelly, palmitic acid, oleic acid, and myristylmyristate.

Surfactants can include polysorbates, sorbitan esters, poloxamer, orsodium lauryl sulfate. In one embodiment, the surfactant is sodiumlauryl sulfate.

Metal chelators can include physiologically acceptable chelating agentsincluding edetic acid, malic acid, or fumaric acid. In one embodiment,the metal chelator is edetic acid.

pH adjusters can also be utilized to adjust the pH of a solutioncontaining tanaproget to about 4 to about 6. In one embodiment, the pHof a solution containing tanaproget is adjusted to a pH of about 4.6. pHadjustors can include physiologically acceptable agents including citricacid, ascorbic acid, fumaric acid, or malic acid, and salts thereof. Inone embodiment, the pH adjuster is citric acid.

Additional fillers that can be used in the composition of the presentinvention include mannitol, calcium phosphate, pregelatinized starch, orsucrose.

D. Methods of Using the Compositions

The invention further provides a method of delivering tanaproget to apatient, where the method includes administering a micronized tanaprogetdosing unit according to the invention.

The dosage requirements of tanaproget may vary based on the severity ofthe symptoms presented and the particular subject being treated.Treatment can be initiated with small dosages less than the optimum doseof tanaproget. Thereafter the dosage is increased until the optimumeffect under the circumstances is reached. Precise dosages will bedetermined by the administering physician based on experience with theindividual subject treated. In general, the compositions of thisinvention are most desirably administered at a concentration that willgenerally afford effective results without causing any unacceptableharmful or deleterious side effects. For example, an effective amount ofmicronized tanaproget is generally, e.g., about 1 mg, about 0.15 mg,about 0.2 mg, or about 0.3 mg.

These compositions containing micronized tanaproget are therefore usefulin contraception and hormone replacement therapy. The compositions arealso useful in contraception and the treatment and/or prevention ofuterine myometrial fibroids, benign prostatic hypertrophy, benign andmalignant neoplastic disease, dysfunctional bleeding, uterineleiomyomata, endometriosis, polycystic ovary syndrome, and carcinomasand adenocarcinomas of the pituitary, endometrium, kidney, ovary,breast, colon, and prostate and other hormone-dependent tumors, and inthe preparation of medicaments useful therefor. Additional uses of thecompositions include stimulation of food intake.

The compositions of the invention are formed into a suitable dosing unitfor delivery to a patient. Suitable dosing units include oral dosingunits, such as a directly compressible tablets, caplets, capsules,powders, suspensions, microcapsules, dispersible powders, granules,suspensions, syrups, elixirs, and aerosols. In one embodiment, thecompositions of the present invention are compressed into a tablet orcaplet, which is optionally added to a capsule, or the compositions areadded directly to a capsule. The compositions of the invention can alsobe formulated for delivery by other suitable routes. These dosing unitsare readily prepared using the methods described herein and those knownto those of skill in the art.

Solid forms, including tablets, caplets, and capsules containingmicronized tanaproget can be formed by dry blending tanaproget with thecomponents described above. In one embodiment, the capsules utilized inthe present invention include hydroxypropyl methylcellulose(hypromellose) capsule, or a hard shell gelatin capsule. In anotherembodiment the tablets or caplets of the present invention that containtanaproget are film-coated. Suitable film-coatings are known to those ofskill in the art. For example, the film-coating can be selected fromamong polymers such as hydroxypropylmethylcellulose, ethyl cellulose,polyvinyl alcohol, and combinations thereof. More desirable tablet orcaplet weights include tablets or caplets of about 100 mg, about 150 mg,about 200 mg, or about 300 mg. However, tablets or caplets of lesser orgreater weights can be utilized as determined by one of skill in theart.

A pharmaceutically effective amount of tanaproget can vary depending onthe components of the composition, mode of delivery, severity of thecondition being treated, the patient's age and weight, and any otheractive ingredients used in the composition. The dosing regimen can alsobe adjusted to provide the optimal therapeutic response. Several divideddoses can be delivered daily, e.g., in divided doses 2 to 4 times a day,or a single dose can be delivered. The dose can however beproportionally reduced or increased as indicated by the exigencies ofthe therapeutic situation. In one embodiment, the delivery is on adaily, weekly, or monthly basis. In another embodiment, the delivery ison a daily delivery. Daily dosages can also be lowered or raised basedon the periodic delivery.

It is contemplated that when the compositions of this invention are usedfor contraception or hormone replacement therapy, they can beadministered in conjunction with one or more other progesterone receptoragonists, estrogen receptor agonists, progesterone receptor antagonists,and selective estrogen receptor modulators, among others.

When utilized for treating neoplastic disease, carcinomas, andadenocarcinomas, they can be administered in conjunction with one ormore chemotherapeutic agents, which can readily be selected by one ofskill in the art.

E. Kits of the Invention

The present invention also provides kits or packages containingmicronized tanaproget. Kits of the present invention can includetanaproget and a carrier suitable for administration to a mammaliansubject as discussed above. In one embodiment, the tablets, caplets, orcapsules are packaged in blister packs, and in a further embodiment,Ultrx™ 2000 blister packs.

The kits or packages containing the compositions of the presentinvention are designed for use in the regimens described herein. In oneembodiment, these kits are designed for daily oral delivery over 21-day,28-day, 30-day, or 31-day cycles, among others, or for one oral deliveryper day. When the compositions are to be delivered continuously, apackage or kit can include the composition in each tablet or caplet.When the compositions of the present invention are to be delivered withperiodic discontinuation, a package or kit can include placebos on thosedays when the composition is not delivered.

Additional components may be co-administered with the composition of theinvention and include progestational agents, estrogens, and selectiveestrogen receptor modulators.

In one embodiment, the kits are organized to indicate a single oralformulation or combination of oral formulations to be taken on each dayof the cycle, in a further embodiment including oral tablets or capletsto be taken on each of the days specified, and in still a furtherembodiment one oral tablet or caplet will contain each of the combineddaily dosages indicated.

In one embodiment, a kit can include a single phase of a daily dosage ofthe composition of the invention over a 21-day, 28-day, 30-day, or31-day cycle. Alternatively, a kit can include a single phase of a dailydosage of the composition of the invention over the first 21 days of a28-day, 30-day, or 31-day cycle. A kit can also include a single phaseof a daily dosage of the composition of the invention over the first 28days of a 30-day or 31-day cycle.

In a further embodiment, a kit can include a single combined phase of adaily dosage of the composition of the invention and a progestationalagent over a 21-day, 28-day, 30-day, or 31-day cycle. Alternatively, akit can include a single combined phase of a daily dosage of thecomposition of the invention and a progestational agent over the first21 days of a 28-day, 30-day, or 31-day cycle. A kit can also include asingle combined phase of a daily dosage of the composition of theinvention and a progestational agent over the first 28 days of a 30-dayor 31-day cycle.

In another embodiment, a 28-day kit can include a first phase of from 14to 28 daily dosage units of the composition of the invention; a secondphase of from 1 to 11 daily dosage units of a progestational agent; and,optionally, a third phase of an orally and pharmaceutically acceptableplacebo for the remaining days of the cycle.

In yet a further embodiment, a 28-day kit can include a first phase offrom 14 to 21 daily dosage units of the composition of the invention; asecond phase of from 1 to 11 daily dosage units of a progestationalagent; and, optionally, a third phase of an orally and pharmaceuticallyacceptable placebo for the remaining days of the cycle.

In another embodiment, a 28-day kit can include a first phase of from 18to 21 daily dosage units of the composition of the invention; a secondphase of from 1 to 7 daily dose units of a progestational agent; and,optionally, an orally and pharmaceutically acceptable placebo for eachof the remaining 0 to 9 days in the 28-day cycle.

In yet a further embodiment, a 28-day kit can include a first phase of21 daily dosage units of the composition of the invention; a secondphase of 3 daily dosage units for days 22 to 24 of a progestationalagent; and, optionally, a third phase of 4 daily units of an orally andpharmaceutically acceptable placebo for each of days 25 to 28.

In another embodiment, a 28-day kit can include a first phase of from 14to 21 daily dosage units of a progestational agent equal inprogestational activity to about 35 to about 150 μg levonorgestrel, asecond phase of from 1 to 11 daily dosage units of the composition ofthe invention; and optionally, a third phase of an orally andpharmaceutically acceptable placebo for the remaining days of the cyclein which no antiprogestin, progestin or estrogen is administered.

In a further embodiment, a 28-day kit can include a first phase of from14 to 21 daily dosage units of a progestational agent equal inprogestational activity to about 35 to about 100 μg levonorgestrel; asecond phase of from 1 to 11 daily dosage units of the composition ofthe invention; and optionally, a third phase of an orally andpharmaceutically acceptable placebo for the remaining days of the cyclein which no antiprogestin, progestin or estrogen is administered.

In one embodiment, the daily dosage of tanaproget remains fixed in eachparticular phase in which it is delivered. In a further embodiment, thedaily dose units described are to be delivered in the order described,with the first phase followed in order by the second and third phases.To help facilitate compliance with each regimen, in a further embodimentthe kits contain the placebo described for the final days of the cycle.

A number of packages or kits are known in the art for the use indispensing pharmaceutical agents for oral use. In one embodiment, thepackage has indicators for each day of the 28-day cycle, and in afurther embodiment is a labeled blister package, dial dispenser package,or bottle.

The kit can further contain instructions for administering thetanaproget compositions of the present invention.

The following examples are provided to illustrate the invention and donot limit the scope thereof. One skilled in the art will appreciate thatalthough specific reagents and conditions are outlined in the followingexamples, modifications can be made which are meant to be encompassed bythe spirit and scope of the invention.

EXAMPLES Example 1 Preparation of Micronized Tanaproget

Tanaproget was prepared according to US Patent Application PublicationNo. 2005/0272702, published Dec. 8, 2005, was milled using a U-10 Comilmill and thereby micronized using a MC50 Jetpharma Micronizer with aEZFH-1.4 Feeder. Particle size was tested periodically for a particlesize of less than about 15 μm, and desirably less than about 10 μm,being distributed throughout 50% of the sample. The micronizedtanaproget was packed in triple poly-bagged fiber drums. A desiccant wasinserted between the outermost bags and the atmosphere in the bagsreplaced with nitrogen gas.

Example 2 Preparation of Compositions and Tablets Containing MicronizedTanaproget

This example provides the preparation of tablets containing micronizedtanaproget using the components of Table 5.

TABLE 5 Component Function Specification Micronized tanaproget Activeingredient In-house Microcrystalline Cellulose Filler, Granulation NFaid, Disintegrant Anhydrous Lactose Filler NF Sodium thiosulfatepentahydrate Antioxidant USP Edetate Calcium Disodium HydrousAntioxidant USP Croscarmellose Sodium Disintegrant NF Magnesium StearateLubricant NF/EP Opadry ™ II Blue Coating material In-house

Tablets containing micronized tanaproget were prepared according to thefollowing granulation. See, Table 6. If the total wt/wt % of thecomponents exceeded 100%, the amount of anhydrous lactose was adjustedby reducing or increasing the amount of anhydrous lactose in thecomposition.

TABLE 6 Tablet Strength (mg) 100 150 200 300 Amount Amount Amount AmountComponent (mg) % wt/wt (mg) % wt/wt (mg) % wt/wt (mg) % wt/wtIntragranular Micronized tanaproget 0.1051 0.1546 0.1575 0.2316 0.2100.3088 0.315 0.4632 MCC 27.20 40.00 27.20 40.00 27.20 40.00 27.20 40.00Anhydrous lactose 37.312 54.8706 37.260 54.7935 37.207 54.7163 37.10254.5619 EDTA 0.068 0.10 0.068 0.10 0.068 0.10 0.068 0.10 micronizedsodium thiosulfate 0.34 0.5 0.34 0.5 0.34 0.5 0.34 0.5 pentahydratemicronized croscarmellose 1.36 2.00 1.36 2.00 1.36 2.00 1.36 2.00 sodiummagnesium stearate 0.1275 0.1875 0.1275 0.1875 0.1275 0.1875 0.12750.1875 Extragranular Croscarmellose sodium 1.36 2.00 1.36 2.00 1.36 2.001.36 2.00 Magnesium stearate 0.1275 0.1875 0.1275 0.1875 0.1275 0.18750.1275 0.1875 Total (Core Tablet Weight) 68.00 100.00 68.00 100.00 68.00100.00 68.00 100.00 Opardy II Blue 2.38 3.5 2.38 3.5 2.38 3.5 2.38 3.5Purified Water* — qs — qs — qs — qs *Not present in final dosage form.

Microcrystalline Cellulose (MCC) and anhydrous lactose were mixed in asuitable size PK-Blender equipped with intensifier bar for 1 minutewithout activating the intensifier bar. A second portion of anhydrouslactose was added to a canister and the canister was rotated for 1minute to dust the walls of the canister with the anhydrous lactose.Micronized tanaproget, sodium thiosulfate and EDTA were added to thecanister and mixed for 1 minute. The content of the canister was thenemptied into the PK-blender. A portion of anhydrous lactose was used torinse the emptied canister for 1 minute and was then transferred to thePK-blender. Croscarmellose sodium was added to the PK-blender. Theremaining MCC and anhydrous lactose were added to the PK-blender. Theblender was mixed, for a certain amount of time at an appropriate mixingspeed, depending on the size of the blender, with and without theintensifier bar [e.g., 20 revolutions per minute (rpm) for 13 minuteswith intensifier bar inactivated, followed by 4 minutes with theintensifier bar activated, and followed by 1 minute with the intensifierbar inactivated]. Intragranular magnesium stearate was added to thePK-Blender and mixed for 2 minutes without the intensifier baractivated. The blend from step 8 was discharged from the PK Blender intoa double poly-lined container. The blend was then compacted and milledusing an Alexanderwerk roller compactor. The milled material wastransferred to a suitable size PK-Blender and mixed for 1 minute.Extragranular croscarmellose sodium was added to the PK-blender andmixed for 10 minutes without the intensifier bar activated.Extragranular magnesium stearate was added to the blender and mixed for2 minutes without the intensifier bar activated. The blend wasdischarged from the PK-blender into a tarred double poly-linedcontainer. The tablets were thereby prepared by compressing the finalblend into 68 mg tablets using a rotary tablet press equipped with 7/32″(0.2187″) round modified concave tooling.

The tablets were coated using a film coat suspension by first preparingan Opadry™ II Blue suspension by slowly adding the Opadry™ II Blue towater with continuous agitation. The tablets were loaded into anappropriate size pan of a coating machine and a sufficient film-coatsuspension was applied to provide around 3.5% average dry-coat weightper tablet.

Example 3 Variation of MCC, Croscarmellose Sodium, and MagnesiumStearate Concentrations in Tanaproget Compositions

In this Example, ten (10) compositions containing tanaproget, EDTA,sodium thiosulfate, anhydrous lactose and varying amounts of MCC,croscarmellose sodium, and magnesium stearate were prepared according tothe procedure set forth in Example 2 and using the components set forthin Tables 7 and 8. The remaining portion of the composition was adjustedusing anhydrous lactose to obtain a total % wt/wt of 100 as noted inTable 8.

TABLE 7 Component % wt/wt Micronized tanaproget 0.1546 EDTA 0.10micronized sodium 0.5 thiosulfate pentahydrate Purified Water* qs *Notpresent in final dosage form.

TABLE 8 % wt/wt Croscarmellose Magnesium Anhydrous Run MCC SodiumStearate Lactose 1 40 4 0.375 54.87 2 30 6 0.5 62.745 3 50 2 0.5 46.7454 50 6 0.5 42.745 5 30 2 0.5 66.745 6 30 6 0.25 63.0 7 50 6 0.25 43.0 840 4 0.375 54.87 9 50 2 0.25 47.0 10 30 2 0.25 77.0

Example 4 Variation of Excipient Concentration in TanaprogetCompositions

In this Example, twelve (12) compositions containing fixed amounts oftanaproget and EDTA and varying amounts of MCC, croscarmellose sodium,magnesium stearate, sodium thiosulfate, anhydrous lactose, and cysteinewere prepared using the components set forth in Table 9 and theprocedure set forth below.

50% of the MCC and 40% of the anhydrous lactose were passed through a#40 mess screen, transferred to a PK-Blender, and mixed for 1 minute.10% of the lactose was added to a bag and mixed with sodium thiosulfate,cysteine, and EDTA, passed through a #40 mesh screen and added to the PKblender containing the MCC. Tanaproget was added to another bag, mixed,passed through a #40 mesh screen, and added to the PK blender. 10% ofthe lactose was passed through a #40 screen, used to rinse the bag thatcontained the tanaproget, and added to the PK-blender. Thecroscarmellose sodium was passed through a #40 screen and added to theblender. The remaining MCC and lactose were also passed through a #40screen and added to the blender.

The material in the blender was blended for 12 minutes without theintensifier bar, followed by 3 minutes with the intensifier bar, andthen an additional 1 minute without the intensifier bar. Magnesiumstearate was passed through a #40 screen, added to the blender, andmixed. The blend from the PK-blender was then roller compacted andmilled using an Alexanderwerk roller compactor and mill running.

The compacted and milled granulation was transferred to a PK-blender andmixed. Extragranular croscarmellose sodium was passed through a #40 meshscreen, added to the PK blender, and mixed. Extragranular magnesiumstearate was passed through a #40 mesh screen, added to the PK-blender,and mixed to form the final blend.

The blend was compressed into 68 mg tablets using an instrumented KorshXL100 tablet press with 7/32″ modified concave B tooling. The tabletswere also coated with a 20% Opadry II blue dispersion.

TABLE 9 Run (% wt/wt) Component 1 2 3 4 5 6 7 8 9 10 11 12 IntragranularMicronized 0.1545 0.1545 0.1545 0.1545 0.1545 0.1545 0.1545 0.15450.1545 0.1545 0.1545 0.1545 tanaproget MCC 40.00 30.00 50.00 50.00 30.0030.00 50.00 40.00 50.00 30.00 40.00 40.00 Anhydrous 54.3705 62.245546.2455 42.2455 66.2455 62.4955 42.4955 54.3705 46.4955 66.4955 54.920553.8205 lactose micronized L- 0.50 0.50 0.50 0.50 0.50 0.50 0.50 0.500.50 0.50 0.25 0.75 cysteine micronized 0.10 0.10 0.10 0.10 0.10 0.100.10 0.10 0.10 0.10 0.10 0.10 EDTA Disodium 0.50 0.50 0.50 0.50 0.500.50 0.50 0.50 0.50 0.50 0.25 0.75 thiosulfate Croscarmellose 2.00 3.001.00 3.00 1.00 3.00 3.00 2.00 1.0 1.00 2.00 2.00 sodium Magnesium 0.1880.25 0.25 0.25 0.25 0.125 0.125 0.188 0.125 0.125 0.188 0.188 stearateExtragranular Croscarmellose 2.00 3.00 1.00 3.00 1.00 3.00 3.00 2.001.00 1.00 2.00 2.00 sodium Magnesium 0.187 0.25 0.25 0.25 0.25 0.1250.125 0.187 0.125 0.125 0.187 0.187 stearate Opadry Blue — — — — — — —3.00 — — 3.00 3.00

Example 5 Variation of Antioxidant Concentrations in TanaprogetCompositions

In this Example, three (3) compositions containing micronizedtanaproget, MCC, croscarmellose sodium, and magnesium stearate andvarying amounts of sodium thiosulfate and EDTA were prepared accordingto the procedure set forth in Example 2 and using the components setforth in Tables 10 and 11. The remaining portion of the composition wasadjusted using anhydrous lactose to obtain a total % wt/wt of 100 asnoted in Table 11.

TABLE 10 Component % wt/wt Micronized tanaproget 0.1546 MCC 40 magnesiumstearate 0.375 croscarmellose sodium 4 Purified Water* qs *Not presentin final dosage form.

TABLE 11 % wt/wt Sodium Anhydrous Run Thiosulfate EDTA Lactose 1 0.250.05 55.17 2 0.5 0.1 54.87 3 0.75 0.15 54.57

All documents listed in this specification are incorporated herein byreference. While the invention has been described with reference to aparticularly preferred embodiment, it will be appreciated thatmodifications can be made without departing from the spirit of theinvention. Such modifications are intended to fall within the scope ofthe appended claims.

What is claimed is:
 1. A process for preparing a pharmaceuticalcomposition comprising micronized tanaproget or a pharmaceuticallyacceptable salt thereof, said process comprising: (i) mixing a firstportion of microcrystalline cellulose and a first portion of anhydrouslactose; (ii) mixing the product of step (i) with a second portion ofanhydrous lactose; (iii) mixing the product of step (ii) with micronizedtanaproget, micronized sodium thiosulfate pentahydrate, and micronizededetate calcium disodium hydrous; (iv) mixing the product of step (iii)with a first portion of croscarmellose sodium; (v) mixing the product ofstep (iv) with a second portion of microcrystalline cellulose and athird portion of anhydrous lactose; and (vi) mixing the product of step(v) with a first portion of magnesium stearate.
 2. The process accordingto claim 1, further comprising: (vii) compacting and milling the productof step (vi).
 3. The process according to claim 2, further comprising:(viii) mixing the product of step (vii) with a second portion ofcroscarmellose sodium; and (ix) mixing the product of step (viii) with asecond portion of magnesium stearate.
 4. The process according to claim3, further comprising: (x) compressing the product of step (ix) into atablet or caplet.
 5. The process according to claim 4, wherein saidtablet or caplet is a 100 mg, 150 mg, 200 mg, or 300 mg tablet orcaplet.
 6. The process according to claim 4, further comprising: (xi)coating said tablet or caplet.
 7. The process according to claim 6,further comprising: (xii) drying said coating.
 8. The process accordingto claim 3, further comprising: (x) mixing the product of step (ix) witha fourth portion of anhydrous lactose.
 9. The process according to claim8, further comprising: (xi) adding the product of step (x) to a capsule.10. The composition according to claim 1, wherein the particles of saidmicronized tanaproget are less than about 10 μm.
 11. The compositionaccording to claim 1, wherein the particles of said micronized sodiumthiosulfate pentahydrate are less than about 31 μm.
 12. The compositionaccording to claim 1, wherein the particles of said micronized sodiumedetate calcium disodium hydrous are less than about 35 μm.
 13. Thecomposition according to claim 3, wherein the product of step (ix)comprises about 0.15% to about 0.50% wt/wt of said tanaproget.
 14. Theprocess according to claim 3, wherein the product of step (ix) comprisesabout 0.15% wt/wt micronized tanaproget, about 40% wt/wtmicrocrystalline cellulose, about 4% wt/wt croscarmellose sodium, about54.87% wt/wt anhydrous lactose, about 0.38% wt/wt magnesium stearate,about 0.1% wt/wt micronized edetate calcium disodium hydrous, and about0.5% wt/wt micronized sodium thiosulfate pentahydrate.
 15. The processaccording to claim 3, wherein the product of step (ix) comprises about0.23% wt/wt micronized tanaproget or a pharmaceutically acceptable saltthereof, about 40% wt/wt microcrystalline cellulose, about 4% wt/wtcroscarmellose sodium, about 54.79% wt/wt anhydrous lactose, about 0.38%wt/wt magnesium stearate, about 0.1% wt/wt micronized edetate calciumdisodium hydrous, and about 0.5% wt/wt micronized sodium thiosulfatepentahydrate.
 16. The process according to claim 3, wherein the productof step (ix) comprises about 0.31% wt/wt micronized tanaproget or apharmaceutically acceptable salt thereof, about 40% wt/wtmicrocrystalline cellulose, about 4% wt/wt croscarmellose sodium, about54.71% wt/wt anhydrous lactose, about 0.38% wt/wt magnesium stearate,about 0.1% wt/wt micronized edetate calcium disodium hydrous, and about0.5% wt/wt micronized sodium thiosulfate pentahydrate.
 17. The processaccording to claim 3, wherein the product of step (ix) comprises about0.46% wt/wt micronized tanaproget or a pharmaceutically acceptable saltthereof, about 40% wt/wt microcrystalline cellulose, about 4% wt/wtcroscarmellose sodium, about 54.56% wt/wt anhydrous lactose, about 0.38%wt/wt magnesium stearate, about 0.1% wt/wt micronized edetate calciumdisodium hydrous, and about 0.5% wt/wt micronized sodium thiosulfatepentahydrate.
 18. A process for preparing a pharmaceutical compositioncomprising micronized tanaproget or a pharmaceutically acceptable saltthereof, said process comprising: mixing a first portion ofmicrocrystalline cellulose and a first portion of anhydrous lactose;(ii) mixing a second portion of anhydrous lactose, micronized sodiumthiosulfate pentahydrate, cysteine, and micronized edetate calciumdisodium hydrous; (iii) mixing the products of steps (i) and (ii); (iv)mixing the product of step (iii) with micronized tanaproget; (v) mixingthe product of step (iv) with a third portion of anhydrous lactose; (vi)mixing the product of step (v) with a first portion of croscarmellosesodium; (vii) mixing the product of step (vi) with a second portion ofmicrocrystalline cellulose and a fourth portion of anhydrous lactose;and (viii) mixing the product of step (vii) with a first portion ofmagnesium stearate.
 19. The process according to claim 18, furthercomprising: (ix) compacting and milling the product of step (viii). 20.The process according to claim 19, further comprising: (x) mixing theproduct of step (ix) with a second portion of croscarmellose sodium; and(xi) mixing the product of step (x) with a second portion of magnesiumstearate.